The Role of Nanoliposomal Irinotecan Plus Fluorouracil and Folinic Acid as Second-Line Treatment Option in Patients With Metastatic Pancreatic Ductal Adenocarcinoma

According to the NAPOLI-1 trial, nanoliposomal irinotecan (nal-IRI) plus 5-uorouracil/leucovorin (5-FU/LV) showed improved overall survival compared to uorouracil alone for patients with metastatic pancreatic cancer who previously treated gemcitabine-based therapy. In that trial, Asian patients had frequent dose modication due to hematological toxicity. There has been limited information on the clinical benet and toxicity of this regimen in a real-world setting. Herein, we assessed real-world experience of nal-IRI plus 5-FU/LV in patients with advanced pancreatic cancer after gemcitabine failure. Methods We conducted a single institution retrospective analysis of response, survival and safety in patients who had been treated with nal-IRI with 5-FU/LV. Patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy received nal-IRI (80mg/m 2 ) with 5-FU/LV every 2 weeks. real-world sequential

Since the development of the new combination regimens including FOLFIRNOX (a combination of oxaliplatin, irinotecan, folinic acid and uorouracil) and albumin-bound paclitaxel (nab-paclitaxel) with gemcitabine has improved the survival of patients with metastatic PDAC (mPDAC) [4,5]. In clinical practice, for elderly patients or patients with relatively poor performance status (PS), nab-paclitaxel with gemcitabine is more preferred than FOLFIRINOX due to toxicity concerns [6]. Although, uoropyrimidinebased combination regimens are recommended after gemcitabine-based treatment failure [7], more than half of patients who previously treated with gemcitabine-based therapy are not suitable for FOLFIRINOX due to poor general condition [6,8].
Nanoliposomal irinotecan (nal-IRI) consists of irinotecan free base encapsulated in liposome nanoparticles, which maintain higher intra-tumoral levels of both irinotecan and SN-38 (the active metabolite of irinotecan) compared with conventional irinotecan [9]. In a phase III study (NAPOLI-1), in patients with mPDAC previously treated with gemcitabine-based therapy, nal-IRI combination with uorouracil and folinic acid (5-FU/LV) showed superior survival compared with 5-FU/LV (6.1 months vs. 4.2 months; hazard ratio [HR], 0.67, p = 0.012) and manageable toxicity pro le [10]. According to this results, nal-IRI combined with 5-FU/LV was approved by the FDA to be used as a subsequent therapy following gemcitabine-based treatment in patients with mPDAC.
Patients in NAPOLI-1 trial had heterogeneity of clinical feature such as previous anticancer therapy, and only half of patients were treated with gemcitabine combination regimens. Real-world clinical data about e cacy, safety, and dose reduction of nal-IRI plus 5-FU/LV in patients with mPDAC who previously treated with nab-paclitaxel with gemcitabine as rst-line regimen are scarce [11,12]. Therefore, clinical data are needed for nal-IRI plus 5-FU/LV in a changed clinical environment.
In this study, we retrospectively evaluated the e cacy and safety of nal-IRI plus 5-FU/LV in patients with mPDAC who failed to nab-paclitaxel with gemcitabine and assessed the association between nal-IRI dose intensity and clinical outcomes. Furthermore, we investigated whether the use of nal-IRI with 5-FU/LV as the second-line treatment is reasonable option as a continuum of care treatment algorithm in patients with mPDAC.

Patients
This is a single-institution, retrospective, observational analysis including patients diagnosed with mPDAC at the Catholic University of Korea, Seoul St. Mary's Hospital from January 2015 to December 2020. We included patients aged 19 years or older with histologically con rmed either recurrent or metastatic PDAC, who have failed to gemcitabine-based treatment as rst-line palliative therapy. Other key inclusion criteria were a Eastern Cooperative Oncology Group (ECOG) PS 0-2 and measurable or evaluable lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria and adequate hematological (hemoglobin > 9.0 g/dL, white blood cell count > 4000/mm 3 , absolute neutrophil count > 1000/mm 3 , platelet count > 100 000/mm 3) , renal (creatinine < 1.5-fold higher than the upper normal limit) and hepatic functions (total bilirubin < 1.5-fold higher than the upper normal limit, serum transaminase < 3-fold higher than the upper normal limit).

Treatment
Patients received intravenous infusion of nal-IRI at a dose of 80mg/m 2 (equivalent to 70mg/m 2 of irinotecan free base) over 90 min followed by folinic acid 400mg/m 2 over 30 min, then uorouracil 2400mg/m 2 over 46h, every 2 weeks. This treatment course was repeated until disease progression, unacceptable toxicities, or patient's refusal to continue.
Chemotherapy dose and schedule adjustments were allowed. Dose reduction was de ned as a decrease of 15% in the chemotherapy dose relative to the standard regimen in rst three scheduled treatment cycle.
Dose delays were de ned as a delay of ≥ 7 days from the target date in rst three scheduled treatment cycle. Chemotherapy relative dose intensity (RDI) was de ned as the ratio of the delivered dose intensity to the planned dose intensity expressed as percentage. Reduced RDI was de ned as a RDI < 85% from standard dosing, because RDI < 85% has worse survival outcomes in various solid tumors [13].
We did serial computed tomography scans and measured carbohydrate antigen 19 − 9 (CA 19 − 9) at baseline and every 6-8 weeks until disease progression. Radiographic tumor response assessment was analyzed according to RECIST version 1.1. We assessed safety by grading adverse events according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0.

Statistical analysis
The objective response rate (ORR) represented the percentage of patients with a complete response (CR) or partial response (PR) and disease control rate (DCR) represented the percentage of patients with a CR or PR or stable disease (SD) among patients with measurable lesions. Progression-free survival (PFS) was de ned as the time from the rst dose of nal-IRI plus 5-FU/LV to the date of disease progression or death. Overall survival (OS) was estimated from the date of nal-IRI plus 5-FU/LV initiation to the date of death or last follow-up visit.
To assess the e cacy of the entire rst-line and second-line treatment strategy as accurately as possible, we evaluated the PFS 2 and OS 2 in patients who received gemcitabine with nab-paclitaxel as rst-line treatment followed by nal-IRI plus 5-FU/LV as second line therapy. PFS 2 was de ned as the time from the initiation of gemcitabine with nab-paclitaxel to the date of disease progression on nal-IRI plus 5-FU/LV given after rst disease progression, or death. OS 2 was de ned as the time from the beginning of gemcitabine with nab-paclitaxel to the date of death from any cause.
Kaplan-Meier analysis was performed to obtain median OS and median PFS. The HR and 95% con dence intervals (CIs) for OS and PFS were estimated using a strati ed Cox regression model. A multivariate Cox proportional hazards regression model was used to identify the effects of clinical factors on PFS and OS. All tests were two-sided and p-values < 0.05 were considered statistically signi cant. Statistical analyses were performed using IBM SPSS for Window version 24.0 (IBM SPSS Inc., Armonk, New York, USA) and GraphPad Prism version 8.0 (GraphPad Software Inc., San Diego, CA, USA).

Patient characteristics
From January 1, 2015 to December 31, 2020, a total of 51 patients were found to be eligible for this study. The baseline demographics and clinical characteristics are listed in Table 1. Median age was 67 years (range, 50-78) and 30 patients (58.8%) were male. Majority of the patients presented with metastatic disease at the diagnosis and only nine patients (17.6%) had recurrent disease after curative surgery. Serum CA 19 − 9 levels were elevated in 42 (82.4%) of 51 patients with available data at initiation of nal-IRI with 5-FU/LV treatment. Liver (80.4%), lung (31.4%), distant lymph node (31.4%) and peritoneum (29.4%) were most frequent metastatic sites and 8 (15.7%) of total patients had more than three metastases.

Discussion
Since the results of the phase III MPACT trial and the phase III PRODIGE trial, gemcitabine with nabpaclitaxel or FOLFIRINOX has been used as the rst-line treatment for patients with mPDAC [4,5]. As a second-line treatment, for patients who have received prior gemcitabine-based therapy, uoropyrimidinebased chemotherapy regimens are acceptable option. On the other hand, gemcitabine-based treatment can be given to patients who previously treated with uoropyrimidine-based therapy [7]. However, since there are debates about the optimal sequencing strategy for treatment of mPDAC, it is necessary to establish optimal strategy through real-world clinical outcomes. The aim of this study was to evaluate effectiveness and safety of nal-IRI plus 5-FU/LV in patients with mPDAC following gemcitabine-based treatment in a real-world clinical setting. Furthermore, this is the rst analysis to evaluate the survival outcomes from the initiation of rst-line treatment in patients with mPDAC who treated with nal-IRI plus 5-FU/LV as second-line therapy after failure of rst-line gemcitabine with nab-paclitaxel.
The characteristics of the patients in this study were comparable to those of patients enrolled in the NAPOLI-1 trial [10]. With respect to prior treatment, only 55% of patients in the NAPOLI-1 trial received gemcitabine combination treatment, but in this study, most patients (94.1%) were treated with gemcitabine with nab-paclitaxel as rst-line treatment. In addition, in this study, only one patient previously treated with conventional irinotecan containing regimen. Patients who previously progressed on conventional irinotecan had poor survival outcome with nal-IRI plus 5-FU/LV in prior studies [10,11].
Compared to several other real-world study of nal-IRI plus 5-FU/LV, the patients in this study were relatively homogenous in terms of their previous treatment history [11,12].
Concerning the survival outcomes, results of our study demonstrate real world evidence of treatment bene t with nal-IRI plus 5-FU/LV with similar outcome results that reported in the NAPOLI-1 trial (median PFS 2.8 versus 3.1 months, median OS 7.0 versus 6.1 months). In this study, 6-months PFS and OS rate was 27.2% and 62.2%, respectively. These ndings were consistent with the results of the NAPOLI-I trial and prior real-world analyses with Asian population [10,14]. Based on these consistent clinical outcomes, despite difference in patient characteristics, nal-IRI plus 5-FU/LV showed real-world clinical bene t in patients with mPDAC who failed to gemcitabine-based therapy.
With respect to dose modi cation, 33 (64.7%) of 51 patients experienced dose modi cation (dose reduction, n = 30; dose delay, n = 13) during the rst 6weeks. These ndings were consistent with the results that 50 (60%) of 93 patients treated with modi ed dose during the rst 6 weeks in the NAPOLI-I study [15]. Reduced RDI was expected to be associated with poor survival outcomes 13 , but in the current study, reduced RDI was not signi cantly associated with clinical outcomes which is consistent with other previous studies [14,15]. Rather, patients with reduced RDI showed longer PFS, probably because patients who had been treated for a long period of time received more frequent modi ed dose of chemotherapy. Many of patients with mPDAC has deteriorated after rst-line treatment failure, frequent dos e modi cation is necessary due to adverse events. Therefore, appropriate dose modi cation is considered because dose modi cation is not signi cantly associated with survival outcomes. Moreover, according to the post hoc analysis of the NAPOLI-I study, Asian patients had more frequent hematological toxicities than Caucasian patients [16], so active dose adjustment should be considered in Asian patients.
We observed that several baseline characteristics were associated with survival outcome through multivariate analysis. Patients with bone metastases had poor OS, which was consistent with the results of previous real-world study [14]. In prior real-world study, patients with liver metastases showed poor PFS [14]. Also, in analysis of NAPOLI-1 long-term survivals, patients who survived one year more were less likely to have liver metastases [17]. However, in the current study, no association between liver metastases and survival outcome was observed. The subgroup analysis on metastatic burden indicates a better prognosis for the patients with less than three metastases. NLR at the baseline was signi cantly associated with worse OS in the updated analysis of NAPOLI-1 trial [17], but not in this study. Because the prognosis for patients with mPDAC remains poor, there are critical needs to evaluate a biomarker related to the e cacy of nal-IRI plus 5-FU/LV and select patients for optimal treatment based on prognostic biomarkers.
Our results concerning adverse events are also comparable with the results previously reported in the NAPOLI-1 study, except that grade 3 or 4 diarrhea was less observed (5.9% vs. 13%), and grade 3 or 4 neutropenia (58.8% vs. 27%) was more frequently occurred. The safety pro le in our study was consistent with the results of the Asian subgroup analysis of NAPOLI-1 trial including grade 3 or 4 diarrhea (5.9% vs. 3.0%) and grade 3 or 4 neutropenia (58.8% vs. 54.5%) [16]. Most patients were tolerable to treatment, and 11% of patients discontinued treatment because of any adverse events. According to analysis of population pharmacokinetics of nal-IRI, the ethnic differences of adverse events could be associated with blood level of uncapsulated SN-38 [18]. Dose modi cation of nal-IRI should be considered for Asian population because dose modi cation did not affect survival outcomes and neutropenia occurred frequently at standard dose.
Although, gemcitabine with nab-paclitaxel or FOLFIRINOX recommended as rst-line treatment in patients with mPDAC, according to several real-world analysis, rst-line FOLFIRINOX could only be applied in 20-40% of advanced mPDAC patients due to higher incidence of hematological toxicity [19,20]. Therefore, gemcitabine with nab-paclitaxel could be considered as rst-line treatment for the rest of 50-60% patients with mPDAC. Current National Comprehensive Cancer Network guidelines for the treatment of patients with mPDAC, 5-FU-based combination regimens are recommended as second-line therapy after gemcitabine-based treatment failure [7]. However, there is no universally accepted standard regimen for patients with mPDAC after gemcitabine with nab-paclitaxel. Nal-IRI plus 5-FU/LV could be considered in patients with poor PS, due to relatively manageable toxicities. Additionally, unlike with the oxaliplatin plus 5-FU/LV regimen, nal-IRI plus 5-FU/LV is not associated peripheral neuropathy. Therefore, nal-IRI plus 5-FU/LV should be considered as a treatment option considering that patients who received gemcitabine with nab-paclitaxel, are more likely had peripheral neuropathy.
The two rst-line treatment options, gemcitabine with nab-paclitaxel and FOLFIRINOX, have not been compared in the rst-line setting. This means that currently the optimal rst-line treatment and therapeutic sequence are unknown for patients with mPDAC. In the current study population, the median OS from the start of rst-line chemotherapy with gemcitabine plus nab-paclitaxel was 16.3 months.
Excluding patients ongoing of nal-IRI plus 5-FU/LV, 20 (45.5%) of 44 patients received best supportive care and 24 (54.5%) patients received a third line of chemotherapy after disease progression on nal-IRI plus 5-FU/LV. According to previous prospective studies, for patients who treated with gemcitabine with nab-paclitaxel following FOLFIRINOX, the median OS from the initiation of rst-line chemotherapy was 14.2-18.0 months [21,22]. Compared to these studies, sequential treatment of nal-IRI plus 5-FU/LV after gemcitabine with nab-paclitaxel is a reasonable sequential treatment strategy. A comparative prospective randomized trial is needed to con rm optimal sequential treatment strategy for patients with mPDAC.
There are some limitations in our study. First this is retrospective analysis conducted in a single center.
Second, relatively small sample size limits the interpretation of subgroup analysis. Third, dose modi cation and treatment discontinuation were left to the discretion of the physicians, not according to the speci ed protocol. In addition, variability in response assessment intervals can have effect on the results for PFS.